TRANSFORMING GROWTH-FACTOR-BETA-1 REGULATES AXON-SCHWANN CELL-INTERACTIONS

We have investigated the potential regulatory role of TGF-beta in the interactions of neurons and Schwann cells using an in vitro myelinatin g system. Purified populations of neurons and Schwann cells, grown alo ne or in coculture, secrete readily detectable levels of the three mam malian isoforms of TGF-beta; in each case, virtually all of the TGF-be ta activity detected is latent. Expression of TGF-beta 1, a major isof orm produced by Schwann cells, is specifically and significantly downr egulated as a result of axon/Schwann cell interactions. Treatment of S chwann cells or Schwann cell/neuron cocultures with TGF-beta 1, in tur n, has dramatic effects on proliferation and differentiation. In the c ase of purified Schwann cells, treatment with TGF-beta 1 increases the ir proliferation, and it promotes a pre- or nonmyelinating Schwann cel l phenotype characterized by increased NCAM expression, decreased NGF receptor expression, inhibition of the forskolin-mediated induction of the myelin protein PO, and induction of the Schwann cell transcriptio n factor suppressed cAMP-inducible POU protein. Addition of TGE-beta 1 to the cocultures inhibits many of the effects of the axon on Schwann cells, antagonizing the proliferation induced by contact with neurons , and, strikingly, blocking myelination. Ultrastructural analysis of t he treated cultures confirmed the complete inhibition of myelination a nd revealed only rudimentary ensheathment of axons. Associated defects of the Schwann cell basal lamina and reduced expression of laminin we re also detected. These effects of TGF-beta 1 on Schwann cell differen tiation are likely to be direct effects on the Schwann cells themselve s which express high levels of TGF-beta 1 receptors when cocultured wi th neurons. The regulated expression of TGE-beta 1 and its effects on Schwann cells suggest that it may be an important autocrine and paracr ine mediator of neuron/Schwann cell interactions. During development, TGF-beta 1 could serve as an inhibitor of Schwann cell proliferation a nd myelination, whereas after peripheral nerve injury, it may promote the transition of Schwann cells to a proliferating, nonmyelinating phe notype, and thereby enhance the regenerative response.